Platform for transdermal formulations (ptf)

ABSTRACT

A composition which can be used as platform for transdermal administration of therapeutically active compounds and/or nutrients. The composition comprises at least one therapeutically active compound and/or at least one nutrient, and a non-oily emulsion.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application of InternationalApplication No. PCT/IB2003/03467, filed on Jun. 21, 2003, which claimspriority of German Application No. 102 28 680.9, filed Jun. 27, 2002.

DESCRIPTION OF THE PRIOR ART

This invention relates to compositions that allow permeation of smallmolecules, ionic compounds and polypeptides through the skin and theiruse for the manufacture of a medicament that can be utilized to treatspecific conditions and diseases in humans and animals by transdermaldelivery of medicinals, therapeutically active agents and/or nutritionalagents.

As it is well known, transdermal delivery of pharmaceutically activeingredients which are absorbed through the skin into the underlyingblood vessels has the advantage over conventional administration formsfor oral or other parenteral applications of providing a controllableplasma level in the therapeutic range while at the same time avoidingthe therapeutic dose to fall short or be exceeded. Hence, transdermaldrug delivery is a convenient and reliable form of administeringmedicinals.

Transdermal delivery may particularly benefit patients with chronicdisease. Many such patients have difficulty following regimens requiringseveral doses daily of medications that repeatedly cause unpleasantsymptoms. They find the same drugs much more acceptable whenadministered in transdermal systems that require applicationinfrequently—in some cases, only once or twice weekly—and that reduceadverse effects.

Transdermal delivery has been referred to in many circles as the“delivery system of the future”. In the last few years, medicalresearchers have realized that many nutrients are more effectivelydelivered via the skin (the body largest organ) than by oral means. Manynutrients cannot be effectively absorbed when taken orally because thestomach acids destroy them and/or the liver discards them. Transdermaldelivery absorbs more than 90% of most hormones compared to less than 5%when taken orally.

A further advantage of transdermal drug delivery lies in the fact thatthe gastro-intestinal tract and the portal system are circumvented. As aresult, it is not necessary to take into account the first-pass effect,which requires high doses of medicinal agents within oral administrationforms. Such high doses of medicinal agents are often responsible forplasma peaks involving undesired side effects.

Transdermal application permits the use of a much broader range of drugsand natural substances for therapeutic application, in particular drugswhich have short half-lives in the body such as hormones. Suchsubstances would have to be taken many times daily by other ordinarydosage forms. Continuous transdermal delivery provides a practical wayof administration and one that can mimic the body's own patterns ofsecretion.

In summary, transdermal drug delivery, as compared to “traditional”routes, has the following advantages:

-   -   It avoids the need for gastrointestinal absorption.    -   It avoids the first-pass effect.    -   It permits multiple therapies with single application.    -   It extends the activity of drugs with short half-lives.    -   In many cases, it provides the capacity to terminate drug        effects rapidly.    -   It allows rapid identification of the medication in emergency        situations.

Typical systemically active agents that may be delivered transdermallyare therapeutic agents that are sufficiently potent and thus can bedelivered through the skin to the blood steam in sufficient quantitiesto produce the desired therapeutic effect. In general, this includestherapeutic agents in all of the major therapeutic areas. The majorrestriction for the treatment of specific conditions and diseases bytransdermal delivery of medicinal agents is the capability of medicinalsto be absorbed through the skin. Many known medicinals are either notskin absorbable or are absorbed at rates insufficient for therapeuticpurposes. In particular, transdermal delivery of either ionic compoundsor large polypeptides has not been achieved successfully yet.

Considerable research efforts have been invested in the attempts todeliver polypeptides and ions through the skin. Most of the solutionsthat were suggested involved complicated and expensive methods. A recentreview summarized a large part of these studies with an emphasis on asimple method that was referred to as “lipid-base delivery system”, see:Foldvari, M et al., Biotechnol. Appl. Biochem., 30:129-137 (1999).

Several transdermal therapeutic devices exist and are marketed, however,all exist as products for “small” molecular weight drugs and non-ioniccompounds. Transdermal therapeutic devices for delivery of either ioniccompounds or large polypeptides do not exist yet.

SUMMARY OF THE INVENTION

It was, therefore, a main object of the present invention to provide acomposition for the manufacture of medicaments which provide improvedtransdermal delivery of molecules and drugs, in particular ofpolypeptides and/or ionic compounds.

It has surprisingly been found that a non-oily emulsion can providerapid permeation of an active ingredient through the skin and into theblood vessels, wherein the active ingredient can be selected, forexample, from the group comprising small molecules, ionic compounds andpolypeptide hormones.

An advantage of the non-oily emulsion is that ionic compounds (e.g.ferrous ions) and polypeptides with a molecular weight of up to 7000Dalton such as, for example, insulin are enabled to permeate the skin. Afurther advantage of the non-oily emulsion is the remarkably quickabsorption of an active ingredient into the circulation.

In a preferred embodiment of the composition, the non-oily emulsioncomprises a mixture of lecithin(s), bile salts and cholesterol in water.

Lecithins are glycero-phospholipids that are formed by fatty acids,glycerol, phosphoric acid and choline. Naturally occurring lecithins arederivatives of the 1,2-diacyl-sn-glycerol-3-phosphoric acids. The largenumber of different lecithins results from varying fatty acid residues.One always obtains a mixture of lecithins when they are extracted frombiological material.

Bile salts are the salts of substituted cholanic acids, which areassociated primarily with glycine or taurins in bile. Cholanic aciditself is not present in bile.

Cholesterol is the major representative of the zoosterols and can befound in virtually all organisms.

Each of the components of the non-oily emulsion, lecithin(s), bile saltsand cholesterol, is preferably present in an amount of between 2 to 15%(w/v), in relation to the non-oily emulsion. It is particularlypreferred that the components of the mixture are present in a ratio byweight of 2:1:1 (lecithin:bile salt:cholesterol).

It is preferred that the sum of the amounts of lecithins, bile salts andcholesterol constitutes 6-30% (w/v) of the non-oily emulsion.

In a preferred embodiment, the composition for transdermaladministration of therapeutically active compounds and/or nutrientsfurther comprises an organic sulfur compound.

The organic sulfur compound is preferably present in an amount of 2-30%(w/v) and more preferably in an amount of % (w/v), in relation to thenon-oily emulsion.

The organic sulfur compound is preferably selected from the groupcomprising dimethylsulfoxide, methylsulfonylmethane (MSM),2,3-dimethylsulfolane and 2,4-dimethylsulfolane and sodium laurylsulfate, wherein MSM is particularly preferred.

U.S. Pat. No. 6,183,758 discloses a skin absorbent cream comprising of acombination of two separate solutions. The first solution consists ofwater, MSM and urea. The other solution contains propylene glycol and amedication or molecular organic compound such as a steroid, alkaloid ornutrient.

The composition for transdermal administration of active compoundsaccording to the present invention has universal applications and canserve as platform for the manufacture of medicaments for transdermaldelivery of molecules and drugs such as non-steroidal anti-inflammatorydrugs (NSAIDs), e.g. ibuprofen. The composition is particularly suitablein assisting the permeation of polypeptides with a molecular weight ofup to 7,000 Dalton and/or ionic compounds.

Examples for polypeptides that can be administered through the skinutilizing the composition of the present invention are insulin,glucagon, calcitonin and various other peptide hormones.

For a review on the transport of peptide and protein drugs through theintestinal, buccal, nasal and pulmonary absorptive membranes, as well astransdermal penetration, see: Verhoef, J. C., Eur. J Drug Metab.Pharmacokinet., 15(2): 83-93 (1990).

Examples for ionic compounds that can be administered through the skinutilizing the composition of the present invention are ferrous fumarate,ferrous sulphate, ferrous glutamate, calcium, zinc and various otherions.

Insulin, in particular, is extremely important for the treatment ofDiabetes Mellitus, a serious pathologic condition that represents the4^(th) leading cause of death in the United States. Diabetes Mellitus,due to inadequate insulin secretion or lack of insulin is extremelywidespread. Treatment of this disease (especially under severeconditions) by injections or infusion of insulin is predominantly viathe subcutaneous route and to a minor extent via the intravenous orintramuscular routes. These methods of administration have thedisadvantage that once given they cannot be withdrawn, e.g. in cases ofhypoglycemia or other adverse effects. It is important to note that upto 7% of deaths in insulin-dependent diabetics have been attributed tohypoglycemia. Although subcutaneous insulin replacement therapy hassaved countless lives, it has become clear over the last few years thatthis non-physiologic insulin administration is far from being optimal inforestalling cardiovascular and neurological complications associatedwith the disease.

Thus, there would be a great advantage in administering insulin (and forthat matter other proteins and polypeptides) transdermally, in that atransdermal patch can be readily withdrawn in case of adverse effectsdeveloping in a patient. Moreover, transdermal administration is a moreconvenient and user-friendly mode of drug administration, compared to,e.g., the daily injection regimen which is widely used clinically at thepresent time in the case of insulin. Extensive research into theadministration of insulin, either by transdermal or by other routes, hasnot resulted in any practical and simple clinical use till now.

Various techniques were tested and described in the literature for thedelivery of insulin through the skin. For example, the ultrasonicvibration technique, tested on hairless mice immersed in a bath ofneutral aqueous insulin, see: Tachibana, K. et al., J. Pharm.Pharmacol., 43(4): 270-1 (1991). The use of various emulsions of insulinin treating rabbits or diabetic rats was described by Shichiri, M etal., in Diabetologia, 10: 317-21 (1974) and in Diabetes, 24: 971 (1975).Transdermal delivery of insulin in mice by using lecithin vesicles as acarrier was recently described by Guo, J. et al., Drug Deliv., 7(2):113-116 (2000). Many other examples, none leading so far to practicalsolution, were described in the open literature.

With reference to the attached Figures, it is illustrated that the PTFof the present invention is a safe and efficient way to administermedicinals through the skin of a patient. In particular, the PTF of thepresent invention allows ionic compounds and peptide hormones to beadministered readily through the patient's skin.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: The effect of the novel insulin PTF on plasma glucose levels ina healthy subject.

FIG. 2: The effect of the novel insulin PTF on plasma glucoseconcentration (percent change from baseline levels) following 75 g sugarload, in a healthy subject, with and without insulin patch.

FIG. 3: The effect of an acute administration of the novel insulin PTFon plasma glucose levels of a type II diabetic subject.

FIG. 4: The effect of two prolonged applications of the novel insulinPTF on plasma glucose levels of a type II diabetic subject.

FIG. 5: The effect of glucagon in the novel PTF on plasma glucose levels(percent change versus time zero) following 75 g sugar load in a healthysubject.

FIG. 6: The effect of ferrous sulfate containing patch, applied tocalves' ears, on ferrous concentration in their plasma.

FIG. 7: The effect of ibuprofen containing patch, applied to rabbits'skin, on their plasma ibuprofen concentration.

FIG. 8: Calcitonin plasma concentrations in calves, followingapplication of a patch with PTF containing calcitonin (averages±SEM).

FIG. 9: The effect of calcitonin containing PTF patch on theconcentration of calcium in calves.

FIG. 10: Triclabendazole (TCBZ) concentration in plasma of cows treatedwith PTF patch, with and without ivermectin (averages±SD; N=5).

FIG. 1: Ivermectin concentration in plasma of cows treated with PTFpatch, with and without triclabendazole (TCBZ) (averages±SD; N=5).

The efficiency, safety and universal applicability of the PTF of thepresent invention will be illustrated by way of examples. It should beunderstood that these examples are in no way restricting the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION EXAMPLE 1

A patch of the novel PTF was soaked with an emulsion of the presentinvention comprising of a non-oily emulsion, MSM and insulin (formulaI). The patch was applied to a healthy volunteer after establishing thesubject's glucose baseline. Glucose baseline was determined to beapprox. 102 mg/dl (mg %). Subsequent blood glucose levels were measuredapproximately half an hour apart. FIG. 1 illustrates that blood glucoseconcentration was reduced by 5 to 8%.

Such a moderate decline in blood glucose concentration could beattributed to a feedback mechanism that decreases the synthesis andsecretion of endogenous insulin. This result demonstrates the safetyquality of transdermal application of insulin utilising the non-oilyemulsion of the invention, because it is unlikely that hypoglycemia willoccur upon inadvertent use of an insulin patch based on the transdermalformulation platform of the invention.

EXAMPLE 2

The PTF containing insulin in the specific non-oily emulsion (formula I)did not exhibit a major effect on blood glucose level when applied to anormal healthy subject (example 1). To demonstrate the efficiency of thetransdermal formulation platform of the invention, it was further testedon another healthy subject that was loaded with 75 g sugar. Afterestablishing glucose baseline of the healthy volunteer, the subject wasloaded with 75 g of sugar dissolved in water. Blood glucose levels weremonitored for the next two hours. In another experiment with the samesubject, at least one week apart, the PTF patch soaked with the emulsionaccording to formula I was applied for half an hour (FIG. 2) and thenthe subject was offered an identical sugar load of 75 g in water.

As can be seen in FIG. 2, the area under the curve for glucoseconcentration over time (in which baseline levels were assigned thevalue of 100%) was about 50% smaller for the sugar load followingapplication of the insulin patch compared to the area after a controlsugar load.

EXAMPLE 3

A similar experiment to example 2 was repeated in the same healthysubject, except that MSM was omitted from the non-oily emulsion (FIG. 2,Formula II). A patch, which was soaked with the non-oily emulsion madeof lecithins, bile salts and cholesterol containing insulin, was appliedto the subject. Almost one hour later, the subject was loaded with 75 gof sugar dissolved in water. Blood glucose levels were monitored for oneand a half hours. The PTF patch was removed and at this point thesubject was approximately 20% hypoglycemic compared to his own baseline.As seen in FIG. 2, the area under the curve for glucose concentrationover time was similar to that for Formula I and significantly lower thanthe area under the curve for the control sugar load. In this specificcase, the non-oily emulsion without MSM worked almost equally well asthe one containing MSM.

EXAMPLE 4

A PTF patch was soaked with an emulsion of the present inventioncomprising of a non-oily emulsion, MSM and insulin (formula I). Thepatch was applied onto a type II diabetic subject, who was regularlytreated with a biguanide drug (metformin hydrochloride, 850 mg t.i.d.),and a sulfonylurea drug (repaglimide, 2 mg t.i.d.), with no insulintreatment. The morning of testing the subject did not take any drugtreatment and started with baseline glucose concentration around 184mg/dl. Following application of the patch, glucose concentrationgradually decreased during the next three hours by 23% (see FIG. 3). Atthis point the PTF patch was removed. During the next hour an additionaldecrease of 3% in blood glucose was observed which might be due to aninsulin depot in the skin. However an hour later and after consumingsome food, the levels increased again to the starting high levels. Atthis stage the subject resumed his regular drug treatment.

These experimental data unequivocally demonstrate the efficiency of thePTF in transdermal administration of insulin.

EXAMPLE 5

In two experiments, in two different occasions, another type II diabeticsubject was treated for a whole day with prolonged application of onepatch of the PTF, soaked with an emulsion of the present inventioncomprising of a non-oily emulsion, MSM and insulin. The subject wasregularly under treatment of a sulfonylurea drug (glibenclamide, 5 mgb.i.d.) with no insulin treatment. On testing days he took no medicationand started with baseline glucose levels in the range of 240-260 mg/dl.4-8 hours following patch application his glucose levels were in thenormal range (see FIG. 4). After each experiment, following one day oftreatment with the patch, the subject reported glucose levels around 150mg/dl with his usual drug therapy.

EXAMPLE 6

The universality of the non-oily emulsion of the invention in inducingskin penetration of peptides is demonstrated in another example.Glucagon is a 3.5 kDa peptide whose high levels are known to inhibitglycolysis and stimulate gluconeogenesis. It is extensively degraded inliver, kidney and plasma and therefore its half-life is 3-6 minutes. Todemonstrate the penetration of glucagon through the skin, the followingexperiment was conducted on a healthy volunteer. On two differentoccasions, the percent change in plasma glucose compared to time zero(time of sugar load) was followed in the same volunteer after 75 g ofsugar load, with and without glucagon PTF (applied 45 minutes before thesugar load). Patch application prolonged dramatically the duration ofthe decrease in glucose concentration, which declined rapidly onlyfollowing patch removal (see FIG. 5).

EXAMPLE 7

The non-oily emulsion in the PTF of the invention is extremely effectivein enhancing the penetration of ions through the skin, as shown in thefollowing example.

The bioavailabilty of iron and adverse effects of its oraladministration are a source of continuing concern, e.g. see: Thorand, B,et al., Southeast Asian J Trop. Med. Public Health, 24(4): 624-30(1993). Iron administration was studied, among others, in calves, e.g.see: Geisser, P. et al., Arzneimittelforschung, 41(1): 32-37 (1991).

A patch of the novel PTF was soaked with an emulsion of the presentinvention comprising of a non-oily emulsion, MSM and ferrous sulphate(salt concentration should be adjusted to the range 10-20%). The patchwas applied to the ears of three calves whose average ferrousconcentration in plasma was 245 μg/dl. After 3.5 hours ferrous plasmaconcentration reached a level of 410 μg/dl (see FIG. 6). Ferrous plasmalevels declined rapidly after removal of the patch (4.6 hours followingapplication).

EXAMPLE 8

The PTF is obviously capable also of inducing the penetration of smallmolecules and drugs through the skin. The NSAID ibuprofen, was studied,as many other drugs, for its percutaneous bioavailability, e.g. see:Kleinbloesem, C. H., et a., Arzneimittelforschung, 45(10): 1117-21(1995).

A pad of the novel PTF with the non-oily emulsion containing ibuprofenchloride was applied to the skin of three rabbits (see FIG. 7).

Adjustment of plasma levels to a preferred therapeutic concentration(around 10 μg/ml) can be easily achieved by varying the concentration ofibuprofen in the mixture and/or the size of the patch, as is the commonpractice in transdermal patches.

EXAMPLE 9

Human calcitonin is a 32 amino acid peptide hormone (MW 3,527),synthesized in the C-cells of the thyroid gland. Calcitonins (especiallysalmon calcitonin, MW 3,432) have been recognized as effective drugs forseveral diseases, including hypercalcemia, Paget's disease andosteoporosis. Calcitonins are rapidly inactivated when given by mouthand therefore their administration relies on either parenteral injectionor recently also nasal spray. Intensive efforts have been devoted to thetransdermal (mainly iontophoretic) delivery of salmon calcitonin, e.g.see: Chang, S L et a., Intern. J. Pharmac. 200:107-113 (2000).

During the last few years, the importance of daily low-dose intermittenttreatments with parathyroid hormone (hPTH 1-34) for the increase in boneformation in postmenopausal women has immerged, e.g. see: Rehman, Q etal., Osteoporos Int, 14:77-81(2003). To avoid the inconvenient dailyinjections of this 34 amino acid peptide hormone, which markedlyaffected compliance, attempts had also been made to deliver ittransdermally, e.g. through the use of pulsatile iontophoresis, see:Suzuki, Yet al., J. Pharm. Pharmacol. 53:1227-1234 (2001). Thepossibility of sequential therapy with the two hormones, PTH andcalcitonin, was also suggested.

The novel PTF provides a new approach to enable a simple and convenienttransdermal delivery of these closely associated hormones, for thetreatment and prevention of osteoporosis. To prove the feasibility ofthe proposed method, a study of the transdermal delivery of calcitoninwas initiated in calves.

A patch containing the novel PTF with 600 IU of salmon calcitonin and aprotease inhibitor was applied to the ears of three calves whose averagecalcitonin-like immunoreactivity in plasma was 163 pg/ml. Three othercalves were treated with control placebo patches. The patches wereapplied for 4 hours. One hour after calcitonin patch application and upto one hour following removal of the patch, calcitonin immunoreactivityin the plasma of the treated calves was higher than that found in theplacebo treated (see FIG. 8). In addition, the physiological effect ofcalcitonins, namely lowering of calcium concentration in plasma, wasalso recorded (see FIG. 9), especially during two hours following the 4hours patch treatment.

EXAMPLE 10

Parasitic infections, caused by pathogenic protozoa or helminths(worms—nematodes, trematodes or cestodes), affect over 3 billion peopleall around the world, with helminthiasis itself affecting over 2billion, particularly in tropical regions. Due to the intensive humantravel and migration of our age, there is a realistic threat of wormsspreading to geographic locations that previously had been consideredfree of the parasites. Parasites infect also domestic animals to a largeextent (e.g. flukes), imposing a substantial health and economic burden.

Many antiparasitic agents were developed originally for veterinary useand only later were adapted to human beings. One example is ivermectin(MW 875), an insoluble drug used extensively to control and treat abroad spectrum of infections caused by parasitic nematodes andarthropods (insects, ticks, and mites) that infect livestock anddomestic animals. It was also recently found to be quite successful inthe human treatment of scabies. Triclabendazole (TCBZ), anotherinsoluble drug used successfully in veterinary medicine, showedconsiderable promise for treating human infections (e.g. paragonimiasis,enterobiasis etc.). Formulations of ivermectin with triclabendazole wereshown to be very effective against liver fluke (Fasciola hepatica),gastrointestinal nematodes in cattle and sheep and sucking lice speciesin cattle. Another common parasiticide, emetine, is a drug used to treatinfections of the liver, bowel and intestine caused by amoebae,including ameobic dysentery. It is a bitter and somewhat poisonousalkaloid that is administered by injection (which may be painful) andirritates the stomach lining and other mucous membranes.

The transdermal application of parasticides can offer an excellentsolution to many drug administration difficulties and have an enormouslyimportant economic value for the use in livestock and domestic animals.

Another important use of the transdermal application is for specificcases of antibiotic treatment. In several gastrointestinal pathologicalstates (e.g. the use of erythromycin for the treatment of gastroparesis)the transdermal route may offer an optimal solution to otherwise erraticdrug administration.

To demonstrate the value of the novel PTF for treatment withantiparasitic agents, a solution of 400 mg/ml of TCBZ in the PTF wasused. The study was carried out in 5 cows, around 200 kg each, treatedtransdermally with 6 ml. Blood samples were taken during the 5 daystudy, and the patch was removed about 18 hours before the last sample.TCBZ was determined by extraction of plasma samples and reversed phaseHPLC, using UV-detection.

TCBZ is metabolized rapidly to its sulphoxide (TCBZ-SO) and sulphone(TCBZ-SO2) derivatives following administration, active metabolites thatare eliminated slowly. Following oral dosing, very little, if any,unchanged drug is detected in animals plasma. In the current study,following transdermal application (see FIG. 10), considerable amount ofTCBZ was detected in the first sample, 3 hours after application of thepatch. The concentration of the drug was quite constant for 72 hours,somewhat dropping only in the last sample, 18 hours after patch removal.

To test the possibility of a combined TCBZ+ivermectin treatment, 5similar cows were treated with PTF patch containing both TCBZ and 100mg/ml of ivermectin. The pharmacokinetic profile was quite similar (seeFIG. 10), only this time TCBZ concentrations were about 70% higher. Inadditional 5 cows, ivermectin alone was used and compared to the mixtureivermectin+TCBZ (see FIG. 11). Though ivermectine is persistentlyinsoluble and it has quite a large molecular weight, plasma analysisexhibited continuously stable concentrations of the drug for theduration of the 4 days study. In the drug combination of ivermectinTCBZ, the concentration of ivermectin was somewhat lower on the secondday of treatment, but otherwise reasonably stable over the treatmentperiod.

The non-oily emulsion of the present invention provides a platform fortransdermal formulations that are universally applicable and allows themanufacture of medicaments for transdermal administration of smallmolecules, ionic compounds, antiparasitic agents, anthelmintics,antibiotics and/or polypeptides with a molecular weight of up to 7000Dalton, for human treatment and/or for the treatment of animals.

What has been described above are preferred aspects of the presentinvention. It is of course not possible to describe every conceivablecombination of components or methodologies for purposes of describingthe present invention, but one of ordinary skill in the art willrecognize that many further combinations and permutations of the presentinvention are possible. Accordingly, the present invention is intendedto embrace all such alterations, combinations, modifications, andvariations that fall within the spirit and scope of the appended claims.

1. A composition for transdermal administration of at least onetherapeutically active compound or nutrient, said compositioncomprising: at least one item selected from the group consisting of atleast one therapeutically active compound and at least one nutrient; anda non-oily emulsion.
 2. The composition for transdermal administrationaccording to claim 1, wherein said at least one therapeutically activecompound and said at least one nutrient is an ionic compound.
 3. Thecomposition for transdermal administration according to claim 2, whereinthe ionic compound is a metal ion.
 4. The composition according to claim1, wherein said at least one therapeutically active compound is apolypeptide.
 5. The composition according to claim 4, wherein saidpolypeptide has a molecular weight of up to 7000 kDa.
 6. The compositionaccording to claim 1, wherein said at least one therapeutically activecompound is selected from the group consisting of antiparasitic agents,anthelmintic drugs and antibiotic drugs, used for the treatment ofhumans, livestock or domestic animals.
 7. The composition according toany one claim 1, wherein said non-oily emulsion is a mixture oflecithin, bile salt and cholesterol.
 8. The composition according toclaim 7, wherein, said lecithin is present in said non-oily emulsion inan amount of 2-15% (w/v), said bile salt is present in said non-oilyemulsion in an amount of 2-15% (w/v), and said cholesterol is present insaid non-oily emulsion in an amount of 2-15% (w/v).
 9. The compositionaccording to claim 7, wherein the ratio by weight of lecithins, bilesalts and cholesterol is 2:1:1.
 10. The composition according to claim8, wherein the sum of the amounts of lecithins, bile salts andcholesterol constitutes 6-30% (w/v) of the non-oily emulsion.
 11. Thecomposition according to claim 1, wherein the composition furthercomprises an organic sulfur compound.
 12. The composition according toclaim 11, wherein, the organic sulfur compound is present in saidcomposition in an amount of 2-30% (w/v), in relation to the non-oilyemulsion.
 13. The composition according to claim 11, wherein the organicsulfur compound is selected from the group consisting ofdimethylsulfoxide, methylsulfonylmethane, 2,3-dimethylsulfolane,2,4-dimethylsulfolane and sodium lauryl sulfate.
 14. Use of thecomposition according to claim 1 for the manufacture of a cream, gel,lotion, suppositories, ointment, patch (TTS) for transdermaladministration of active substances, preferably nutrients and/ormedications.
 15. Use of the composition according to claim 1 fortransdermal administration of active substances, preferably nutrientsand/or medications.
 16. The composition according to claim 12, whereinthe organic sulphur compound is present in said composition in an amountof 4-25% (w/v), in relation to said non-oily emulsion.